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Hypoxia-Inducible Factor-1 (HIF-1)

Nelson Institute of Environmental Medicine, New York University, School of Medicine, Tuxedo, New York

Adaptation to low oxygen tension (hypoxia) in cells and tissues leads to the transcriptional induction of a series of genes that participate in angiogenesis, iron metabolism, glucose metabolism, and cell proliferation/survival. The primary factor mediating this response is the hypoxia-inducible factor-1 (HIF-1), an oxygen-sensitive transcriptional activator. HIF-1 consists of a constitutively expressed subunit HIF-1 and an oxygen-regulated subunit HIF-1 (or its paralogs HIF-2 and HIF-3). The stability and activity of the subunit of HIF are regulated by its post-translational modifications such as hydroxylation, ubiquitination, acetylation, and phosphorylation. In normoxia, hydroxylation of two proline residues and acetylation of a lysine residue at the oxygen-dependent degradation domain (ODDD) of HIF-1 trigger its association with pVHL E3 ligase complex, leading to HIF-1 degradation via ubiquitin-proteasome pathway. In hypoxia, the HIF-1 subunit becomes stable and interacts with coactivators such as cAMP response element-binding protein binding protein/p300 and regulates the expression of target genes. Overexpression of HIF-1 has been found in various cancers, and targeting HIF-1 could represent a novel approach to cancer therapy.

Address correspondence to: Dr. Max Costa, Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987. E-mail: costam01{at}nyu.edu

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